OBJECTIVE: Describe sex differences in outcomes and response to spironolactone in patients with heart failure with preserved ejection fraction (HFpEF). BACKGROUND: HFpEF affects women more frequently than men. Sex differences in effect of mineralocorticoid antagonists have not been reported. METHODS: This was an exploratory, post-hoc, non-prespecified analysis of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT). Subjects with symptomatic HF and an LVEF ≥45% were randomized to spironolactone or placebo. Subjects enrolled from the Americas were analyzed. The primary outcome was a composite of cardiovascular (CV) death, cardiac arrest, or HF hospitalization. Secondary outcomes included all-cause, CV, and non-CV mortality, and CV, HF, and non-CV hospitalization. Sex differences in outcomes and treatment effect were determined using time-to-event analysis. RESULTS: In total, 882/1767 (49.9%) subjects were women. Women were older with fewer comorbidities but worse patient-reported outcomes. There were no sex differences in outcomes in the placebo arm or in response to spironolactone for the primary outcome or its components. Spironolactone was associated with reduced all-cause mortality in women (HR 0.66, p=0.01), but not in men (p(interaction)=0.02). CONCLUSIONS: In TOPCAT, women and men presented with different clinical profiles and similar clinical outcomes. The interaction between spironolactone and sex in TOPCAT overall and in our analysis was non-significant for the primary outcome, but there was a reduction in all-cause mortality associated with spironolactone in women with a significant interaction. Prospective evaluation is needed to determine whether spironolactone may be effective for treatment of HFpEF in women.